Lab-grown liver raises hopes but draws criticism

Though human cells spontaneously group into rudimentary organs, some scientists say work is very preliminary

LAB LIVER  Lab-made liver cells and umbilical cord cells clustered together in a dish to form three-dimensional liver buds (white dots), a new study reports. However, some scientists question the extent to which the new results advance liver regeneration efforts.

T. Takebe 

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A tiny cluster of lab-grown human cells that sprouts into liver tissue could one day nix the need for organ donors. But the promise has drawn both praise and criticism, with some scientists arguing that the results are unconvincing.

Liver buds transplanted into mice form blood vessels (green) that hook up with the animals’ blood supply. The buds form after researchers mix lab-grown liver cells with umbilical cord cells (red). T. Takebe et al./Nature 2013

Using a new technique to craft mini organs, stem cell biologist Takanori Takebe of Yokohama City University in Japan, and his colleagues report that they created human livers in a dish. After transplantation into mice, the liver cells hooked up to blood vessels and behaved like human livers, Takebe’s team says July 3 in Nature.

“It’s a tantalizing study,” says Ira Fox, a clinician and transplant scientist at Children’s Hospital of Pittsburgh. “But the real issue is that almost nothing they’ve done is complete.”

In the last few years, scientists have figured out how to conjure up different cell types from induced pluripotent stem cells, or iPS cells. Such cells have been reprogrammed back to an embryonic-like state. Dosing them with a chemical concoction can transform them into just about any cell type, including liver cells.

But shepherding iPS cells into adulthood isn’t easy. So Takebe and his colleagues worked on a new method that encourages the liver cells to grow up into organs.

After mixing lab-made liver cells with cells collected from umbilical cords, the team noticed that the commingled cells began to clump together, as if reeled in by invisible wires. “The cells self-assembled and organized into a liver bud,” says Ken Zaret, a developmental biologist at the University of Pennsylvania in Philadelphia. “It’s a remarkable discovery.”

The buds, three-dimensional lumps of cells that resemble a rudimentary liver, pumped out proteins and broke down drugs — as do liver cells harvested from humans and other liver cells that scientists have made from iPS cells. “It’s pretty much what I would expect to happen,” says stem cell biologist Stephen Duncan of the Medical College of Wisconsin in Milwaukee.

Duncan says he is skeptical that Takebe’s liver buds are much better than cells made by other methods. And an experiment meant to showcase the new buds’ value is not convincing, he says.

In that experiment, Takebe tried to prove that the buds can save mice with damaged livers. The researchers grafted buds about the size of a pencil eraser into the abdomens of living mice. Then the researchers damaged the mouse livers, leaving the human buds intact. After one month, about 90 percent of the mice with buds stayed alive, compared with just 20 percent of the mice without bud transplants.

But the researchers watched the animals for too short a time, says vascular biologist Shahin Rafii, of Cornell University. Since the experiment ended after a month, the researchers can’t say whether the mice with buds would have lived much longer.

What’s more, Rafii says, iPS cells are known for forming tumors. Only a longer experiment would show whether the buds cause cancer.

“It’s not the perfect liver,” Takebe acknowledges. He says he would like to improve the buds, and make a more sophisticated organ that includes a bile-duct system.

Still, Fox says that Takebe’s buds seem to be a little better at making protein than cells other researchers have made. “It’s a cute study and I think it’s going to advance the field,” he says. “But is it life changing? No. It’s an incremental improvement.”

After three days growing in a dish, a mixture of lab-grown liver cells and umbilical cord cells can cluster together into a 3-D rudimentary organ.
Credit: Takanori Takebe

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